tbuckley/cabot-search huggingface dataset:
Phase 1 dose escalation and expansion study of bemcentinib (BGB324), a first-in-class, selective AXL inhibitor, with docetaxel in patients with previously treated advanced NSCLC.
Authors: Sheena Bhalla, Farjana J. Fattah, Jessica N. Williams, Alyssa Macchiaroli, Jonathan Padro, Meredith Pogue, Jonathan Dowell, Rolf A. Brekken, William C. Putnam, Nigel William McCracken, David Micklem, Zenobia D'Costa, David E. Gerber
Journal: Journal of Clinical Oncology (2022)

9081 Background: AXL, a transmembrane receptor tyrosine kinase, is overexpressed and associated with poor prognosis and treatment resistance in non-small cell lung cancer (NSCLC). Bemcentinib (BGB324) is a selective orally bioavailable small molecule inhibitor of AXL, currently in phase 2 clinical development, that has demonstrated synergistic activity with docetaxel in in vivo models of NSCLC. This phase I dose escalation and expansion trial assessed the safety, tolerability, and preliminary efficacy of bemcentinib in combination with docetaxel in previously treated advanced NSCLC. Methods: Dose escalation of daily bemcentinib in combination with docetaxel (60 or 75 mg/m 2 every 3 weeks) followed a standard 3+3 design. Bemcentinib monotherapy was administered for one week prior to docetaxel initiation to assess pharmacodynamic effects alone and in combination. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) pre-dose (C1D-7), C1D1, and C2D1. Results: A total of 21 patients (pts) were enrolled with median age 62 (range 39-84) and 67% male. A median of 3 (range 1-13) cycles of therapy were administered. Principal treatment-related adverse events were neutropenia (86%, 76% ≥G3), diarrhea (57%, 0% ≥G3), fatigue (52%, 5% ≥G3), and nausea (52%, 0% ≥G3). Neutropenic fever ≥G3 occurred in 7 (33%) pts. The maximum tolerated dose was 60 mg/m 2 docetaxel plus 200 mg bemcentinib daily with prophylactic G-CSF support. Pharmacokinetics of bemcentinib alone and in combination with docetaxel were highly similar. Among 15 evaluable pts, 4 (27%) pts had partial response and 9 (60%) pts had stable disease as the best radiographic response. Bemcentinib treatment resulted in changes in plasma levels of proteins associated with regulation of sterol synthesis and AKT signaling. Conclusions: Bemcentinib in combination with docetaxel and prophylactic G-CSF support has a manageable safety profile, leads to decreases in systemic factors associated with tumor growth and metastasis, and demonstrates evidence of anti-tumor activity in previously treated, advanced NSCLC. Further studies to identify the patient population most likely to benefit from this regimen are warranted. Clinical trial information: NCT02922777.
Use of the Esophageal Sponge in Directing Food Reintroduction in Eosinophilic Esophagitis
Authors: Jeffrey A Alexander, Karthik Ravi, Thomas C Symrk, Tsung-The Wu, Crystal J Lavey, Debra Geno, Alyssa J Johnson, Ryan J Lennon, Margaret H Collins, Evan S Dellon, David A Katzka
Journal: Clinical Gastroenterology and Hepatology (2022)
Studying the interaction of germ cell tumors with the microenvironment reveals novel factors involved in cisplatin resistance
Authors: M.A. Skowron, K. Eul, A. Stephan, G.A. Wakileh, G.F. Ludwig, C. Söhngen, A. Bister, K. Raba, P. Petzsch, G. Poschmann, K. Stühler, K. Köhrer, P. Albers, D. Nettersheim
Journal: European Urology (2022)
MEDB-30. Subclassification of Group 3/4 medulloblastoma as a potential prognostic biomarker to reduce the dose of craniospinal irradiation in patients with metastatic tumors: A Japanese Pediatric Molecular Neuro-Oncology Group study
Authors: Kohei Fukuoka, Jun Kurihara, Makiko Mori, Yuki Arakawa, Ema Yoshioka, Tomoko Shofuda, Yuko Matsushita, Yuko Hibiya, Satoko Honda, Atsuko Nakazawa, Chikako Kiyotani, Naoki Kagawa, Kai Yamasaki, Ryo Ando, Dai Keino, Yosuke Miyairi, Takuya Akai, Masayuki Kanamori, Joji Ishida, Young-Soo Park, Atsufumi Kawamura, Atsushi Sasaki, Ryo Nishikawa, Isao Date, Motoo Nagane, Katsuyoshi Koh, Koichi Ichimura, Yonehiro Kanemura
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: In patients with medulloblastoma, one of the most significant challenges is to reduce the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients treated using lower-dose CSI rather than standard therapy is important for further reducing the treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and were treated using lower-dose CSI rather than standard-dose radiation therapy. RESULTS: Among the patients, 23 were classified as having a “standard-risk” and 15 as having a “high-risk” according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months. The median CSI dose was 18 Gy in both groups, and 10 patients in the “high-risk” group received a CSI dose of 23.4 Gy or 24 Gy. Molecular subgrouping revealed the “standard-risk” cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the “high-risk” cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 13 of the 16 “standard-risk” patients were subclassified as subtypes I, IV, VI, and VII, which were associated with a good prognosis according to the novel sub-subclassification among Group 3/4 medulloblastomas. However, only 6 of the 15 “high-risk” patients were included in the subtypes. The good prognostic subtype cases among “high-risk” cohort were all survived without recurrence, in contrast to a worse prognosis (5-year progression free survival=33.3%; p=0.01) of the other cases. CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that the novel sub-subclassification of Group 3/4 medulloblastoma may be a promising prognostic biomarker for reducing the dose of CSI in patients with metastatic medulloblastoma.
The role of pancreatoscopy in the diagnostic work-up of intraductal papillary mucinous neoplasms: a systematic review and meta-analysis
Authors: David M. de Jong, Pauline M. C. Stassen, Bas Groot Koerkamp, Mark Ellrichmann, Petko I. Karagyozov, Andrea Anderloni, Leena Kylänpää, George J. M. Webster, Lydi M. J. W. van Driel, Marco J. Bruno, Pieter J. F. de Jonge
Journal: Endoscopy (2022)

Background Confirming the diagnosis, invasiveness, and disease extent of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas is challenging. The aim of this study was to summarize the literature on the efficacy and safety of peroral pancreatoscopy (POP) in the diagnosis of IPMN, including the impact of pre- and intraoperative POP on the management of IPMN. Methods The EMBASE, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar databases were systematically searched for articles. Eligible articles investigated cohorts of patients who underwent POP for (suspected) IPMN. Results 25 articles were identified and included in this review; with 22 of these reporting on the diagnostic yield of POP in IPMN and 11 reporting on the effect of pre- or intraoperative POP on clinical decision-making. Cannulation and observation rates, and overall diagnostic accuracy were high across all studies. Frequently reported visual characteristics of IPMN were intraductal fish-egg-like lesions, hypervascularity, and granular mucosa. Overall, the adverse event rate was 12 %, primarily consisting of post-endoscopic retrograde cholangiopancreatography pancreatitis, with a pooled rate of 10 %, mostly of mild severity. Regarding the impact of POP on clinical decision-making, POP findings altered the surgical approach in 13 %–62 % of patients. Conclusion POP is technically successful in the vast majority of patients with (suspected) IPMN, has a consistently high diagnostic accuracy, but an adverse event rate of 12 %. Data on intraoperative pancreatoscopy are scarce, but small studies suggest its use can alter surgical management. Future studies are needed to better define the role of POP in the diagnostic work-up of IPMN.
Relma-cel (JWCAR029) in relapsed and refractory B-cell non-Hodgkin lymphoma: A two-year survival update of a phase I study.
Authors: Zhitao Ying, Yuqin Song, Jun Zhu
Journal: Journal of Clinical Oncology (2022)

e19555 Background: B-cell non-Hodgkin lymphoma (B-NHL) has a very poor prognosis. Relma-cel (JWCAR029) is a CD19-targeted chimeric antigen receptor T (CAR-T) cell suspension. In a phase I trial performed in November 2017 in Beijing Cancer Hospital, China, JWCAR029 was used to treat relapsed/refractory B-NHL (R/R B-NHL) in adult patients, showing a high response rate and persistent response. This report aimed to update 2-year survival data generated in the above trial. Methods: This was an open-label, dose-escalating phase I study (JWCAR029-001, NCT03344367) involving patients with R/R B-NHL. The patients received a 3-day treatment with the conditioning chemotherapy regimen, consisting of fludarabine (25 mg/m 2 /day) and cyclophosphamide (250 mg/m 2 /day). Then, they received a single dose of intravenous JWCAR029 (25×10 6 , 50×10 6 , 100×10 6 , or 150×10 6 CAR T cells). Two-year PFS and OS after JWCAR029 treatment were evaluated. The data were updated till the cut-off date of January 18, 2021. Results: A total of 23 patients with R/R B-NHL were enrolled, of whom 22 completed single-dose JWCAR029 cell infusion. All patients completed the 2-year follow-up, with a median time of 24.2 (95%CI 24.0-24.3) months. Based on the efficacy analysis set comprising 20 patients, the best ORR and CRR were 85.00% and 70.00%, respectively. In subgroup analysis, 1-year ORR and CRR in patients administered 100×10 6 cells were both 3/5 (60%); they were both 5/8 (62.5%) in those administered 150×10 6 cells. The 1-year and 2-year PFS rates (11 patients censored) were both 55.0%. Median PFS was not reached (95%CI 3.0 months-NA). The 1-year and 2-year PFS rates in patients administered 100×10 6 cells were both 60.0%; these values were both 62.5% in individuals treated with 150×10 6 cells. The 1-year and 2-year OS rates (3 patients censored) were both 68.6%. Median OS was not reached (95%CI 10.4 months-NA). The 1-year and 2-year OS rates in patients administered 100×10 6 cells were both 60.0%; these values were both 75.0% in those treated with 150×10 6 cells. A total of 6 patients (30%) died. No grade 3 and above CRS or NT were found. Conclusions: JWCAR029 was approved in China in September 2021 after the RELIANCE study (NCT04089215) reported its excellent efficacy and tolerable toxicity in the treatment of relapsed/refractory B-cell lymphoma. This report indicated that R/R B-NHL cases could benefit from JWCAR029. R/R B-NHL cases administered JWCAR029 at 100×10 6 or 150×10 6 cells had a promising response rate, with durable PFS and sustained OS benefits after 12 months. The effectiveness and safety of JWCAR029 need to be confirmed in the real-world setting. Clinical trial information: NCT03344367.
Local bladder hyperthermia with concomitant intravesical instillation of Mytomycin C (Synergo®Rite) in patients with non-muscle invasive bladder cancer (NMIBC). The long-term experience of a single center
Authors: A. Buchler, O. Schwarztuch Gildor, I. Sternberg, I. Leibovitch
Journal: European Urology (2022)
COVID-19 omicron variants demonstrated different virulence in infected patients with cancer: The real-world evidence from the National COVID Cohort Collaborative (N3C).
Authors: Qianqian Song, Benjamin Bates, Fang-Chi Hsu, Feifan Liu, Vithal Madhira, Amit Kumar Mitra, Timothy Bergquist, Xiaochun Li, Noha Sharafeldin, Umit Topaloglu, Jing Su
Journal: Journal of Clinical Oncology (2022)

e18672 Background: Comprehensive real-world evidence of the virulence of COVID-19 Omicron, Delta, and Alpha variants as well as the effectiveness of booster vaccinations in patients with cancer are lacking. We aimed to fill in these gaps for cancer patients and provide essential insights on the management of the fast-evolving pandemic by leveraging the nationally-representative electronic medical records from the National COVID Cohort Collaborative (N3C) registry. Methods: The virulence of COVID-19 variants was examined according to severe outcomes of infected patients with cancer, compared with non-cancer patients, using the N3C data between 12/01/2020 and 02/03/2022. Variants were inferred according to the time periods of variant dominance at &gt; 95% accuracy. The Cox proportional hazards model was employed to evaluate the effects of COVID-19 variants, adjusting for age, gender, race/ethnicity, geographic regions, vaccination status, cancer types, smoking status, cancer treatments, and adjusted Charlson Comorbidity Index (CCI). Results: Our study cohort included 114,195 COVID-19 patients with cancer and 160,493 without cancer as control. Among them, 52,539 (21%) were infected by Omicron, 82,579 (33%) by Delta, and 115,200 (46%) by Alpha variants. Prior to the COVID-19 breakthrough infection, 7%, 22%, 3%, and 69% were vaccinated with 1 dose, 2 doses, a booster, or unvaccinated respectively. The proportions of hospitalization and death among patients with vs without cancer were 40% and 7% vs 18% and 0.4%, respectively. Characteristics of the cancer subcohort are summarized in the Table. Our analysis showed dramatically lower risks of severe outcomes for patients who were infected by Omicron (HR 0.42, 95%CI: 0.38 – 0.46) and slightly lower risks for Delta (HR 0.93, 95%CI: 0.89 – 0.98) compared with those infected by Alpha, after adjusting for other demographic clinical risk factors, and vaccination status. This trend remained similar in subgroups of patients with solid tumors, hematologic malignancies, or without cancer. Similar associations were observed when virulence was evaluated in association with mortality. The effectiveness of booster vaccinations varied across sub-cohorts stratified by variants and cancer types. Booster shots reduced the risk of severe outcomes for patients with solid tumors infected by Omicron variant or hematologic malignancies infected by Delta variants. Conclusions: Our work provides up-to-date and comprehensive real-world evidence of the virulence of COVID-19 variants in patients with cancer. Omicron variant showed significantly reduced virulence for different cancer types.[Table: see text]
Retired consultant is struck off over treatment of young transgender patients
Authors: Clare Dyer
Journal: BMJ (2022)

<h3>Background</h3> Khon Kaen Hospital is the second level of trauma excellence centre in Thailand. The numbers of injury were increasing year by year, therefore the continuing quality improvements in trauma care were needed (ie, trauma alert team, MM-death case conference, root cause analysis and trauma quality round). <h3>Objectives</h3> To know the injury epidemiology and to monitor the quality of trauma care. <h3>Methods</h3> To compare the injury and death rate related with mean Injury Severity Scale (ISS) before and after implementation. Injury Surveillance software was used with retrospective database of all injuries between 1 January 2008 and 30 June 2009, all analysed by descriptive statistics (ie, correlation, t test). <h3>Results</h3> The number of injury was of 24 417 cases (male 16 267: female 8150). The trend of injury rate was increasing at 2.4% rate, with a mean age of deaths decreasing from 35.7 to 33.4 years old, bearing male injury rate increasing from 66.6% to 68.3%. It was found that the gender and age had an impact on the severity (p=0.000) and the severity had a significant impact on mortality and survival rate (p=0.000). The admission numbers showed 7860 cases (32%), the survival rate increased from 90.3% to 92.9%, with an increasing mean of ISS from 6.8 to 7.3, while the mortality decreased from 1.64% to 1.39% with stable mean ISS (27.4–27.6). <h3>Conclusion</h3> These results could be used to confirm the quality of trauma care in hospital was improving and the quality improvement activities should be continued and disseminated.
LGG-34. Nephrological impact of BRAF inhibitors in a pediatric population of central nervous system tumors: a single institution experience
Authors: Antonio Verrico, Marco Crocco, Edoardo La Porta, Andrea Angeletti, Enrico Verrina, Valentina Iurilli, Gianluca Piatelli, Gianluca Piccolo, Claudia Milanaccio, Maria Luisa Garrè
Journal: Neuro-Oncology (2022)

Abstract BRAF inhibitors (iBRAF) are under investigations in ongoing clinical trials for pediatric brain tumor treatment. Preliminary data regarding the pediatric population report pyrexia, hematological, dermatological, cardiac, and ophthalmic toxicities among the most common adverse events. Acute kidney injury (AKI), mainly due to tubular interstitial injury, has been reported in the adult population. With our study we want to contribute to a more comprehensive knowledge of the short- and long-term nephrological adverse effects of iBRAF in a pediatric population. We collected and reviewed clinical and laboratory data of all patients treated with iBRAF for pediatric central nervous system tumors at our Institution and available for publication. AKI was monitored through serial creatinine measurements, kidney function with estimated glomerular filtration rate (eGFR) and kidney injury with creatinuria/proteinuria ratio. Tubular injury was evaluated with fractional excretion of sodium, potassium and magnesium and with glycosuria. Moreover, urine was examined to detect presence and morphology of erythrocytes. Eight patients were identified, 3 females; median age at treatment start was 9 years (range 2,75 – 18,75). Six patients with BRAFV600E–mutated pediatric Low-Grade Glioma were treated with Vemurafenib, 1 patient with BRAFV600E-mutated pediatric High-Grade Glioma was treated with Vemurafenib and 1 patient with BRAFV600E-mutated Langerhans Cell Histiocytoses was treated with Dabrafenib. Seven patients were considered for analysis. After a median follow up of 3,83 years (range 2,25 – 6,58) no AKI was reported and all patients but two retained normal eGFR at last follow up. No tubular and glomerular injury laboratory findings were detected, and erythrocytes in the urine resulted always below the upper limit of normality. CONCLUSIONS: iBRAF were not associated with AKI and tubular injury. Nevertheless, some data, namely significative decrease of eGFR in two out of seven patients, warrants further investigations.
Exploiting GLAAD molecules to drive an antitumor immune response in a colorectal cancer mouse model.
Authors: Yemi Adesokan, Marianne Rebecca Spalinger, Romain Wyss, Yong Miao, Michael Scharl
Journal: Journal of Clinical Oncology (2022)

2565 Background: Only a minority of colorectal cancer (CRC) patients benefit from immune checkpoint inhibitors (ICI), with less than half of eligible patients responding to the treatment. Abnormal glycosylation of tumor cells is a signature of cancer development. Here, we described novel immunomodulatory molecules, named GLAAD (glycopeptides with adjuvant and tumor-associated antigen delivery). We hypothesized that GLAAD, by sharing similarities with aberrant glycans expressed in many cancers, may be a safe and effective treatment strategy to promote response and overcome resistance to ICI, thus addressing an urgent clinical need. Using a CRC mouse model, we tested whether two GLAAD candidates reduce tumor burden when orally administered alone or in combination with ICI. Methods: C57/BL6J mice were supplemented with 3% GNU-201 or 3% GNU-101 in the drinking water starting 14 days prior to tumor cell injection (d-14), while control mice received normal drinking water. On day 0, all mice were injected subcutaneously with MC38 CRC cells in each flank. On days 6, 9, 12, and 15, mice in each group received anti-PD1 antibody (aPD1) or an isotype control. Tumor size was measured every 3 rd day. On day 18, the mice were sacrificed. Results: The aPD1 therapy alone showed a limited anti-tumor efficacy overall. Groups treated with GNU-201, GNU-101, GNU-201+aPD1 or GNU-101+aPD1 exhibited reduced growth, resulting in a significantly reduced tumor volume vs control on day 18. In contrast, GLAAD candidates alone significantly reduced tumor volume compared with control and led to a numerically larger decrease than aPD1 treatment alone, suggesting a higher efficacy. When analyzing tumor infiltrating myeloid cells on day 18, no differences were seen for neutrophils or dendritic cells but the proportion of macrophages was decreased in mice receiving GNU-201 or GNU-101. GNU-101 resulted in reduced serum levels of IL-10, a molecule participating in the suppression of antitumor immune responses. The tested GLAAD candidates stimulated robust anti-tumor T cell responses. GNU-201 and GNU-101 supplementation alone or in combination with aPD1 increased the proportion of T cells and among those CD8+ T cells, IFNγ producing CD4+ T cells, IFNγ+ and perforin+ CD8+ T cells. GNU-101 and GNU-201 elicited memory T cell responses after priming of the mice, measured as the ex vivo recall response (CD69 expression) of CD8+ T cells isolated from the tumor. Conclusions: GNU-201 and GNU-101 as standalone treatment induce a strong anti-tumor response that is as good as or even better than aPD1 alone. The therapeutic efficacy is associated with increased tumor infiltration and activation of T cells, in particular CD8+ T cells, highlighting the role of these GLAAD candidates as potent adjuvants in supporting specific tumor-associated antigen recognition by the immune system.
Utility of interval imaging during neoadjuvant treatment of locoregional breast cancer.
Authors: Rebecca Chacko, Pin Li, Nayef Hikmat Abdel-Razeq, Manasi Godbole, Vrushali S. Dabak
Journal: Journal of Clinical Oncology (2022)

e12611 Background: National guidelines for breast cancer management do not recommend routine imaging during preoperative chemotherapy. Despite this, some clinicians use radiographic results as a surrogate marker of treatment response during the preoperative phase. In this retrospective investigation, we studied the correlation between neoadjuvant clinical decision making, midway imaging results and final pathologic responses. Methods: 394 patients with locoregional breast cancer who received neoadjuvant chemotherapy and definitive surgery within the Henry Ford Health System between 2015-2021 were included. Final pathologic response of patients who completed midway imaging were compared with patients who did not. The primary outcome was overall pathologic response rate. Results: Tumor histology and final pathologic response (PR) was compared in patients who received midway imaging (MI) to those who did not (Table). In the MI group, no statistically significant association between midway radiographic response and final PR was found (p = 0.078). Systemic treatment was changed in 14.7% of patients after MI, there was no association with treatment change and complete PR (p = 0.488), however none of patients who received a treatment change after MI had progressive disease on final PR, compared to 9.7% of patients who did not have a treatment change and had progressive disease on final PR (p = 0.035). Multivariate analyses showed no association between MI and complete PR, irrespective of the histological subtypes. 78.4% of patients had imaging at the end of systemic treatment, prior to surgery. Radiographic response on post-treatment imaging correlated with final PR (p &lt; 0.001). Conclusions: This study did not detect an association between midway imaging during neoadjuvant therapy and a complete pathologic response in locoregional breast cancer, however a correlation was detected between post-treatment imaging response and final pathologic response. Changes to systemic treatment based on midway radiographic findings were not shown to improve the likelihood of complete pathologic response but may reduce risk of progressive disease. Based on this study, midway imaging should not be broadly ordered during preoperative treatment, unless there is concern for progressive disease, in which midway imaging may provide diagnostic benefit.[Table: see text]